isbn 978-0-8138-0583-2

Clinical Endocrinology of Companion Anim

als

J a c q u i e R a n d

Clinical Endocrinologyof Companion Animals

editor

ellen n. Behrend, danièlle Gunn-Moore and Michelle L. campbell-Ward section editors

Clinical Endocrinology of Companion AnimalsClinical Endocrinology of Companion Animals offers fast access to clinically relevant information on managing the patient with endocrine disease. Written by leading experts in veterinary endocrinology, each chapter takes the same structure to aid in the rapid retrieval of information, offering information on pathogenesis, signalment, clinical signs, diagnosis, differential diagnosis, treatment, prognosis, and prevention for a broad list of endocrine disorders. Chapters begin with brief summaries for quick reference and then delve into greater detail.

With complete coverage of the most common endocrine diseases, the book includes chapters on conditions in dogs, cats, horses, ferrets, reptiles, and other species. Clinical Endocrinology of Companion Animals is a highly practical resource for any veterinarian treating these common diseases.

Key FeatuRes Provides a quick reference on effectively treating patients with endocrine disorders Offers a consistent presentation for ease of use Covers the most common endocrine diseases encountered in daily practice Written by top veterinary endocrinologists Encompasses small animal, exotic, and equine practice Allows fast access to information in the consulting room or in the field

the editoRJacquie Rand, BSVc, DVSc, MACVS, DACVIM, is Professor of Companion Animal Health at the University of Queensland, Australia. She is also Director of the Centre for Companion Animal Health.

section editoRsellen n. Behrend, VMD, PhD, DACVIM, is Joezy Griffin Professor in Internal Medicine at Auburn University College of Veterinary Medicine.

danièlle Gunn-Moore, BSc, BVM&S, PhD, FHEA, MACVSc, MRCVS, RCVS, Specialist in Feline Medicine, is Professor of Feline Medicine and Head of Companion Animal Sciences at the University of Edinburgh.

Michelle L. campbell-Ward, BSc, BVSc(Hons I), DZooMed(Mammalian), MRCVS, RCVS, Specialist in Zoo and Wildlife Medicine, is Veterinarian at Taronga Western Plains Zoo, Australia.

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Clinical Endocrinology of Companion Animals

Clinical Endocrinology of Companion Animals

Edited by

Jacquie Rand

A John Wiley & Sons, Inc., Publication

This edition first published 2013 © 2013 by John Wiley & Sons, Inc.

Wiley-Blackwell is an imprint of John Wiley & Sons, formed by the merger of Wiley’s global Scientific, Technical and Medical business with Blackwell Publishing.

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Library of Congress Cataloging-in-Publication Data

Clinical endocrinology of companion animals / edited by Jacquie Rand. p. cm. Includes bibliographical references and index. ISBN 978-0-8138-0583-2 (pbk. : alk. paper) 1. Veterinary endocrinology. 2. Pets–Diseases. I. Rand, Jacquie. [DNLM: 1. Endocrine System Diseases–veterinary. 2. Endocrine Glands–physiopathology. 3. Endocrine System Diseases–diagnosis. 4. Pets. SF 768.3] SF768.3.C55 2012 636.089′64–dc23

2012014134

A catalogue record for this book is available from the British Library.

Wiley also publishes its books in a variety of electronic formats. Some content that appears in print may not be available in electronic books.

Cover design by Modern Alchemy LLC

Set in 9.5/11.5pt Sabon by SPi Publisher Services, Pondicherry, India

1 2013

Dedication

This book is dedicated to the important people who shaped my life and goals.My parents, Geoff and Moira, who inspired me to be the best I could be, to never accept mediocrity

from myself, and to always remain optimistic about achieving my goals. They are not here to see the book published, but their legacy remains.

My husband, Tom, who is my greatest supporter, through the challenging times and the good times in life, always there, encouraging me to follow my dreams and be happy.

My daughter, Lisette, who reminds me to maintain a balance in my life and inspires me to be a better role model.

Merlin, our characterful Burmese cat, who has lived a full life despite many twists and turns— surrendered to a municipal animal facility and, on death row, acquired as one of my research cats,

identified as insulin resistant and predisposed to diabetes, adopted into our family—and who sat beside me or on my desk as I wrote and edited chapters for this book.

Thank you all for your inspiration.

vii

Contents

Contributors xPreface xv

1 Hypoadrenocorticism in Dogs 1Patty Lathan

2 Hypoadrenocorticism in Cats 22Danièlle Gunn-Moore and Kerry Simpson

3 Hypoadrenocorticism in Other Species 28Michelle L. Campbell-Ward

4 Critical Illness-Related Corticosteroid Insufficiency (Previously Known as Relative Adrenal Insufficiency) 36Linda Martin

5 Hyperadrenocorticism in Dogs 43Ellen N. Behrend and Carlos Melian

6 Primary Functioning Adrenal Tumors Producing Signs Similar to Hyperadrenocorticism Including Atypical Syndromes in Dogs 65Kate Hill

7 Hyperadrenocorticism in Cats 71Danièlle Gunn-Moore and Kerry Simpson

8 Primary Functioning Adrenal Tumors Producing Signs Similar to Hyperadrenocorticism Including Atypical Syndromes in Cats 80Nicki Reed and Danièlle Gunn-Moore

9 Hyperadrenocorticism in Ferrets 86Nico J. Schoemaker

10 Hyperadrenocorticism and Primary Functioning Adrenal Tumors in Other Species (Excluding Horses and Ferrets) 95Michelle L. Campbell-Ward

11 Hyperadrenocorticism (Pituitary Pars Intermedia Dysfunction) in Horses 100Catherine McGowan

12 Primary Hyperaldosteronism 115Andrea M. Harvey and Kent R. Refsal

viii Contents

13 Pheochromocytoma in Dogs 128Claudia E. Reusch

14 Pheochromocytoma in Cats 137Danièlle Gunn-Moore and Kerry Simpson

15 Canine Diabetes Mellitus 143Linda Fleeman and Jacquie Rand

16 Feline Diabetes Mellitus 169Jacquie Rand

17 Diabetes Mellitus in Other Species 191Michelle L. Campbell-Ward and Jacquie Rand

18 Canine Diabetic Emergencies 201Rebecka S. Hess

19 Feline Diabetic Ketoacidosis 209Jacquie Rand

20 Equine Metabolic Syndrome/Insulin Resistance Syndrome in Horses 217John Keen

21 Insulinoma in Dogs 229Rebecka S. Hess

22 Insulinoma in Cats 240Danièlle Gunn-Moore and Kerry Simpson

23 Insulinomas in Other Species 245Sue Chen and Michelle L. Campbell-Ward

24 Gastrinoma, Glucagonoma, and Other APUDomas 253Craig Ruaux and Patrick Carney

25 Hypothyroidism in Dogs 263David Panciera

26 Hypothyroidism in Cats 273Danièlle Gunn-Moore

27 Hypothyroidism in Other Species 278Janice Sojka Kritchevsky

28 Hyperthyroidism in Dogs 291David Panciera

29 Hyperthyroidism in Cats 295Mark E. Peterson

30 Hyperthyroidism/Thyroid Neoplasia in Other Species 311Michelle L. Campbell-Ward

Contents ix

31 Hypocalcemia in Dogs 315Patricia A. Schenck and Dennis Chew

32 Hypocalcemia in Cats 326Patricia A. Schenck and Dennis Chew

33 Hypocalcemia in Other Species 335Michael Stanford, John Keen and Michelle L. Campbell-Ward

34 Hypercalcemia in Dogs 356Patricia A. Schenck and Dennis Chew

35 Hypercalcemia in Cats 373Dennis Chew and Patricia A. Schenck

36 Hypercalcemia in Other Species 385Michelle L. Campbell-Ward

37 Nutritional Secondary Hyperparathyroidism in Reptiles 396Kevin Eatwell

38 Hyposomatotropism in Dogs 404Annemarie M.W.Y. Voorbij and Hans S. Kooistra

39 Hyposomatotropism in Cats 416Nicki Reed and Danièlle Gunn-Moore

40 Acromegaly in Dogs 421Hans S. Kooistra

41 Acromegaly in Cats 427David Church and Stijn J. M. Niessen

42 Diabetes Insipidus and Polyuria/Polydipsia in Dogs 436Katharine F. Lunn and Katherine M. James

43 Diabetes Insipidus in Cats 450Nicki Reed and Danièlle Gunn-Moore

44 Hyponatremia, SIADH, and Renal Salt Wasting 458Katherine M. James

45 Estrogen- and Androgen-Related Disorders 467Cheri A. Johnson

46 Progesterone and Prolactin-Related Disorders; Adrenal Dysfunction and Sex Hormones 487Cheri A. Johnson

47 Pathologic Reproductive Endocrinology in Other Species 504John Keen and Michelle L. Campbell-Ward

Index 512

x

Contributors

Ellen N. Behrend, VMD, PhD, Dipl. ACVIM (Small Animal Internal Medicine)Joezy Griffin ProfessorDept. Clinical SciencesCollege of Veterinary MedicineAuburn UniversityAuburn, Alabama, USA

Michelle L. Campbell-Ward, BSc, BVSc(Hons I), DZooMed(Mammalian), MRCVSRCVS Specialist in Zoo and Wildlife MedicineTaronga Conservation Society AustraliaTaronga Western Plains Zoo—Wildlife HospitalDubbo, New South Wales, Australia

Patrick Carney, DVM, Dipl. ACVIM (Small Animal Internal Medicine)Staff InternistTufts Veterinary Emergency Treatment & Specialties WalpoleMA Clinical Assistant ProfessorDepartment of Clinical Sciences Cummings School of Veterinary MedicineTufts UniversityNorth Grafton, MA, USA

Sue Chen, DVM, DABVP – Avian PracticeGulf Coast Avian and ExoticsGulf Coast Veterinary SpecialistsHouston, Texas, USA

Dennis Chew, DVM, Dipl. ACVIM (Small Animal Internal Medicine)Professor, EmeritusCenter for Veterinary MedicineDepartment of Veterinary Clinical SciencesCollege of Veterinary MedicineThe Ohio State UniversityColumbus, Ohio, USA

David Church, BVSc, PhD, MACVSc, ILTM, MRCVSRoyal Veterinary CollegeUniversity of LondonLondon, United Kingdom

Contributors xi

Kevin Eatwell, BVSc (hons), DZooMed (Reptilian), Dipl. ECZM (Herp), MRCVSRCVS specialist in Zoo and Wildlife MedicineEuropean Recognised Veterinary Specialist in Zoological Medicine (Herpetological)Lecturer in Exotic Animal and Wildlife MedicineRoyal (Dick) School of Veterinary StudiesUniversity of EdinburghHospital for Small AnimalsEaster Bush Veterinary CentreRoslin, Midlothian, United Kingdom

Linda Fleeman, BVSc, PhD, MANZVSAnimal Diabetes AustraliaRowville Veterinary Clinic, RowvilleBoronia Veterinary Clinic, BoroniaLort Smith Animal Hospital, North MelbourneVictoria, Australia

Danièlle Gunn-Moore, BSc, BVM&S, PhD, FHEA, MACVSc, MRCVSRCVS Specialist in Feline MedicineProfessor of Feline Medicine and Director of Teaching HospitalsRoyal(Dick) School of Veterinary Studies and The Roslin InstituteThe University of EdinburghHospital for Small AnimalsEaster Bush Veterinary CentreRoslin, Midlothian, Scotland

Andrea M. Harvey, BVSc DSAM(Feline) Dipl. ECVIM-CA MRCVSRCVS Specialist in Feline MedicineEuropean Veterinary Specialist in Internal MedicineInternational Society of Feline MedicineWiltshire, United Kingdom

Rebecka S. Hess, DVM, Dipl. ACVIM (Small Animal Internal Medicine)Associate Professor of Internal MedicineChief, Section of MedicineDepartment of Clinical Studies-PhiladelphiaSchool of Veterinary MedicineUniversity of PennsylvaniaPhiladelphia, Pennsylvania, USA

Kate Hill, BVSc, MANZCVSc, Dipl. ACVIM (Small Animal Internal Medicine)Senior LecturerDirector Centre for Service and Working Dog HealthInstitute of Veterinary, Animal and Biomedical ScienceMassey UniversityNew Zealand

Katherine M. James, DVM, PhD, Dipl. ACVIM (Small Animal Internal Medicine)Veterinary Information NetworkDavis, California, USA

Cheri A. Johnson, DVM, MS, Dipl. ACVIM (Small Animal Internal Medicine)Professor and Chief of StaffSmall Animal Clinical SciencesCollege of Veterinary MedicineMichigan State UniversityEast Lansing, Michigan, USA

xii Contributors

John Keen, BSc, BVetMed, PhD CertEM (IntMed), Dipl. ECEIM MRCVSRCVS and European Specialist in Equine Internal MedicineDick Vet Equine HospitalRoyal (Dick) School of Veterinary StudiesEaster Bush Veterinary CentreEaster BushRoslin, Midlothian, United Kingdom

Hans S. Kooistra, DVM, PhD, Dipl. ECVIM-CADepartment of Clinical Sciences of Companion AnimalsFaculty of Veterinary MedicineUtrecht UniversityUtrecht, The Netherlands

Janice Sojka Kritchevsky, VMD, MS, Dipl. ACVIM (Large Animal Internal Medicine)Department of Veterinary Clinical SciencesPurdue University College of Veterinary Medicine WestLafayette, Indiana, USA

Patty Lathan, VMD, MS, Dipl. ACVIM (Small Animal Internal Medicine)Assistant ProfessorDepartment of Clinical SciencesMississippi State University College of Veterinary MedicineStarkville, Mississippi, USA

Katharine F. Lunn, BVMS, MS, PhD, MRCVS, Dipl. ACVIM (Small Animal Internal Medicine)Associate ProfessorDepartment of Clinical SciencesCollege of Veterinary MedicineNorth Carolina State UniversityRaleigh, North Carolina, USA

Linda Martin, DVM, MS, Dipl. ACVECCAssociate Professor, Emergency and Critical CareDepartment of Clinical SciencesCollege of Veterinary MedicineAuburn UniversityAuburn, Alabama, USA

Catherine McGowan, BVSc, MACVSc, DEIM, Dipl. ECEIM, PhD, FHEA, MRCVSSenior Lecturer in Equine Medicine and Director of Veterinary CPDInstitute of Ageing and Chronic Disease,Faculty of Health and Life SciencesUniversity of LiverpoolLeahurst, United Kingdom

Carlos Melian, DVM, PhDDirector of Veterinary Teaching HospitalFaculty of Veterinary MedicineUniversity of Las Palmas de Gran CanariaTrasmontana s/n, 35416 Arucas, Las Palmas, Spain

Contributors xiii

Stijn J. M. Niessen, DVM, PhD, Dipl. ECVIM, PGCVetEd, FHEA, MRCVSLecturer Internal MedicineRoyal Veterinary CollegeUniversity of LondonResearch AssociateDiabetes Research GroupNewcastle Medical SchoolUnited Kingdom

David Panciera, DVM, MS, Dipl. ACVIM (Small Animal Internal Medicine)ProfessorDepartment of Small Animal Clinical SciencesVirginia-Maryland Regional College of Veterinary MedicineVirginia TechBlacksburg, Virginia, USA

Mark E. Peterson, DVM, Dipl. ACVIM (Small Animal Internal Medicine)Director of Endocrinology and Nuclear MedicineAnimal Endocrine ClinicNew York, New York, USA

Jacquie Rand, BVSc, DVSc, MACVS, Dipl. ACVIM (Small Animal Internal Medicine)Professor of Companion Animal HealthDirector, Centre for Companion Animal HealthSchool of Veterinary ScienceThe University of QueenslandAustralia

Nicki Reed, BVM&S, Cert VR, DSAM (Feline), Dipl. ECVIM-CA, MRCVSEuropean Veterinary Specialist in Small Animal MedicineLecturer in Companion Animal MedicineHead of the Feline ClinicRoyal (Dick) School of Veterinary StudiesThe University of EdinburghHospital for Small AnimalsEaster Bush Veterinary CentreRoslin, Midlothian, United Kingdom

Kent R. Refsal, DVM, PhDProfessor, Endocrine SectionDiagnostic Center for Population and Animal HealthMichigan State UniversityLansing, Michigan, USA

Claudia E. Reusch, DVM, Dipl. ECVIM-CAProfessorHead of Clinic for Small Animal Internal MedicineVetsuisse FacultyUniversity of ZurichZurich, Switzerland

Craig Ruaux, BVSc, PhD, Dipl. ACVIM (Small Animal Internal Medicine)Assistant ProfessorDepartment of Veterinary Clinical SciencesOregon State UniversityCorvallis, Oregon, USA

xiv Contributors

Patricia A. Schenck, DVM, PhDSection Chief, Endocrine Diagnostic SectionDiagnostic Center for Population and Animal HealthMichigan State UniversityLansing, Michigan, USA

Nico J. Schoemaker, DVM, PhD, Dipl. ECZM (Small Mammal and Avian), Dipl. ABVP-avianDivision of Zoological MedicineDepartment of Clinical Sciences of Companion AnimalsFaculty of Veterinary Medicine, Utrecht UniversityUtrecht, The Netherlands

Kerry Simpson, BVM&S, Cert VC, PhD, FACVSc (Feline Medicine), MRCVSRCVS Specialist in Feline MedicineThe Feline ExpertLondon, United Kingdom

Michael Stanford, BVSc, FRCVSBirch Heath Veterinary ClinicBirch Heath RoadTarporley, Cheshire, United Kingdom

Annemarie M.W.Y. Voorbij, DVM, MSDepartment of Clinical Sciences of Companion AnimalsFaculty of Veterinary MedicineUtrecht UniversityUtrecht, The Netherlands

xv

Preface

The inspiration for the format of Clinical Endocrinology of Companion Animals was from teaching students in the clinic and consulting with busy veterinarians in busy practices. There was clearly a need for a quick reference guide that had detailed information, but in a format designed to easily find that information. My hope is that this book will provide valuable assistance for clinicians in diagnosing and managing endocrine cases in practice, as well as for students wishing to quickly find information to help with a case or learn in greater depth the details of diseases of the endocrine system. My aim is that this book be a quick reference book for practical use, to be referred to in the consulting room and in the field.

I thank the section editors, Ellen Behrend, Danielle Gunn-Moore, and Michelle Campbell-Ward, for their absolute dedication to making this a quality publication with the most current information known in vet-erinary science on endocrine diseases of the various companion animal species. I also thank the many con-tributors for the richness of their contributions, which represents the sum of many decades of combined knowledge.

I found it fascinating learning of the susceptibility of some exotic companion species to certain endocrine diseases. I hope you also enjoy and find useful the breadth of this book across the common, and not so com-mon, companion animals that veterinarians see in practice.

Clinical Endocrinology of Companion Animals, First Edition. Edited by Jacquie Rand. © 2013 John Wiley & Sons, Inc. Published 2013 by John Wiley & Sons, Inc.

1

Hypoadrenocorticism in DogsPatty Lathan

I. PathogenesisA. Pathophysiology:

1. Most patients with naturally occurring hypoadrenocorticism (“Addison’s disease”) suffer from combined glucocorticoid and mineralocorticoid deficiency:

Pathogenesis

K Primary hypoadrenocorticism results from the destruction of >90% of the adrenal cortex. K Most cases are presumed to be due to an immune-mediated process. K Combined glucocorticoid and mineralocorticoid deficiency occur most frequently, but isolated glu-

cocorticoid deficiency (“atypical hypoadrenocorticism”) is probably underdiagnosed.

Classical Signs

K Young to middle-age dogs are predisposed, as are poodles, West Highland White Terriers, and Great Danes.

K Addison’s disease is known as the “Great Pretender” because nonspecific signs such as lethargy, decreased appetite, and weight loss predominate.

K Gastrointestinal signs such as vomiting and diarrhea are also common. K Patients may present in hypovolemic shock or following collapse.

Diagnosis

K ACTH stimulation test demonstrates minimal cortisol response.

Treatment

K Glucocorticoid and mineralocorticoid supplementation, ± intravenous fluids and supportive therapy.

CHaPter 1

2 Clinical Endocrinology of Companion Animals

a. Aldosterone is a mineralocorticoid secreted in the outermost layer of the adrenal cortex, the zona glomerulosa (Figure 1.1). The major action of aldosterone is the conservation of sodium and water, and excretion of potassium and hydrogen ions (acid), from the distal renal tubule. In normal dogs, secretion of aldosterone is stimulated by hypovolemia and hyperkalemia and is primarily regulated by  the renin-angiotensin-aldosterone system (RAAS). In patients with hypoadrenocorticism and subsequent aldosterone deficiency, hyponatremia, hyperkalemia, and hypovolemia are common.b. Cortisol is a glucocorticoid produced in the inner-most layers of the adrenal cortex, the zonae fasciculata and reticularis. Cortisol has activity in almost every cell in the body. Functions include stimulation of gluconeogenesis and erythropoiesis, maintenance of gastrointestinal mucosal integ-rity, and suppression of the inflammatory response. Additionally, cortisol has important roles in the maintenance of blood pressure and contractility of the heart. Cortisol requirements increase during times of stress. Cortisol release from the adrenal cortex is controlled by adrenocorticotropic hormone (ACTH) (Figure 1.2). Cortisol deficiency in dogs with hypoadrenocorticism may result in gastroin-testinal signs, lethargy, hypoglycemia, hypotension, and anemia.

2. Some patients with hypoadrenocorticism suffer from isolated glucocorticoid deficiency. In these cases, aldosterone secretion is preserved, and electrolyte abnormalities are not present. Patients with isolated gluco-corticoid deficiency are often said to have “atypical hypoadrenocorticism” or “atypical Addison’s disease.”

B. Etiology:1. Primary hypoadrenocorticism results from the destruction of greater than 90% of the adrenal cortex. Most cases of naturally occurring hypoadrenocorticism in dogs are idiopathic, most likely due to immune-mediated destruction of the adrenal cortex. Rarely, infiltration of the adrenal cortex by fungal disease, amyloidosis, or neoplasia has been reported. Trauma, hemorrhage, and infarction may also lead to hypoadrenocorticism.2. Drug-induced adrenocorticolysis can also result in hypoadrenocorticism in dogs being treated for hyperadrenocorticism:

Capsule

Zona fasciculata

Zona glomerulosa

Zona reticularis

Medulla

Figure 1.1 the adrenal cortex is made up of three layers—the zona glomerulosa, zona fasciculata, and zona reticularis. the zone glomerulosa is responsible for mineralocorticoid synthesis, whereas the inner two layers are responsible for glucocorticoid and sex hormone synthesis. (Image provided by Dr. Jim Cooley.)

Hypoadrenocorticism in Dogs 3

a. Adrenocortical necrosis caused by mitotane is usually selective to the zonae fasciculata and retic-ularis, resulting in decreased cortisol production. However, inadequate monitoring or use in a particularly sensitive patient may lead to destruction of the cells of the zona glomerulosa, resulting in aldosterone deficiency as well.b. The other commonly used medication to treat hyperadrenocorticism is trilostane. As an inhibitor of at least one enzyme involved in steroid synthesis (3β-hydroxysteroid dehydrogenase), trilostane overdose may lead to cortisol deficiency and, less frequently, aldosterone deficiency. Additionally, idiosyncratic adrenocortical necrosis has been reported to occur in some dogs taking trilostane, resulting in hypoadrenocorticism.

3. Hypoadrenocorticism secondary to decreased ACTH production is characterized by isolated glucocor-ticoid deficiency since ACTH has little regulatory control of aldosterone production:

a. The most common form of secondary hypoadrenocorticism is iatrogenic, resulting from exoge-nous glucocorticoid administration (Figure 1.3). Exogenous glucocorticoids inhibit the release of adrenocorticotropic hormone (ACTH) from the pituitary gland. Adrenal gland atrophy then occurs, resulting in decreased secretion of cortisol. Following acute withdrawal of the exogenous glucocor-ticoid, a stressful event will cause increased release of ACTH, but the atrophied adrenal glands will be unable to respond by secreting an appropriate amount of cortisol, which may result in signs of cortisol deficiency. Chronic administration of glucocorticoids is more likely to result in hypoadreno-corticism than short-term use, and longer-acting repositol steroids (such as methylprednisolone ace-tate) are more potent suppressors of ACTH than shorter-acting glucocorticoids (such as oral prednisolone). Topical, otic, and ophthalmic preparations containing glucocorticoids may also lead to iatrogenic hypoadrenocorticism, particularly in smaller patients.

Figure 1.2 (a) the hypothalamic pituitary axis without negative feedback. Corticotropin-releasing hormone (CrH) is released by neurons in the hypothalamus and transported to the anterior pituitary by portal circulation. CrH then stimulates the release of aCtH from the pituitary gland into systemic circulation. aCtH then stimulates the synthesis and secretion of cortisol. (b) Negative feedback is the mechanism by which the endocrine system regulates secretion of its hormones. In the HPa-axis, aCtH feeds back to the hypothalamus to inhibit continued release of CrH, which then leads to decreased release of aCtH. Cortisol feeds back to both the hypothalamus to decrease CrH secretion, and to the pituitary gland to decrease aCtH release. By this mechanism, the HPa-axis is able to maintain the physiologically necessary concentration of cortisol in the bloodstream—not too much, nor too little.

Pituitary

ACTHACTH

CortisolCortisol

Hypothalamus

Adrenal Adrenal

CRH

Stress

(a)

Pituitary

ACTHACTH

Cortisol

Hypothalamus

Adrenal Adrenal

CRH

Stress

– – – –

–

(b)

Cortisol

4 Clinical Endocrinology of Companion Animals

b. Naturally occurring causes of secondary hypoadrenocorticism include pituitary masses, trauma, or other lesions that inhibit ACTH release.

4. At this time, the etiology of atypical hypoadrenocorticism (isolated glucocorticoid deficiency) is un known. ACTH deficiency has been ruled out in many cases. It may be the result of partial immune-mediated destruction of the adrenal cortex, sparing the zona glomerulosa. Although some have hypothesized that atypical hypoadrenocorticism is simply an early manifestation of “typical” hypoadrenocorticism, many patients never lose their ability to secrete aldosterone.

C. Risk factors for hypoadrenocorticism:1. Dogs with other immune-mediated endocrinopathies, such as diabetes mellitus and hypothyroidism, may be at increased risk for hypoadrenocorticism.2. Dogs with the disease are more likely to have clinical signs during or following a stressful event.

II. SignalmentA. Any breed of dog may be afflicted with hypoadrenocorticism, including mixed-breeds. However, an increased prevalence of hypoadrenocorticism has been documented in all sizes of poodles, West Highland white terriers, Great Danes, bearded collies, Portuguese water dogs, Leonbergers, Nova Scotia duck-tolling retrievers, and possibly Saint Bernards.B. A genetic basis has been proved in standard poodles, Bearded collies, and Nova Scotia duck-tolling retrievers.C. Young to middle-aged dogs (2–5 years old) are predisposed. However, dogs of any age can be diagnosed with hypoadrenocorticism. Nova Scotia duck-tolling retrievers may be diagnosed at a younger age, as early as 2 months.

Chronic glucocorticoid administration

Clinical signs of hyperadrenocorticism

Adrenocortical atrophy (feedback inhibition)

Abrupt discontinuation of administration

Cortisol deficiency

Clinical signs of hypoadrenocorticism

Figure 1.3 Diagrammatic representation of the relationship between iatrogenic hyperadrenocorticism and iatrogenic hypoadrenocorticism. Chronic glucocorticoid administration leads to clinical signs of glucocorticoid excess (“iatrogenic hyperadrenocorticism”). at the same time, the exogenous glucocorticoid provides feedback inhibition to the pituitary gland, decreasing the production of aCtH. Without aCtH, the dog’s own adrenal glands atrophy. While the dog is still taking the exogenous glucocorticoids, the dog will appear to have hyperadrenocorticism. Upon abrupt withdrawal of the steroid, the dog’s own atrophied adrenal gland will be unable secrete cortisol, potentially resulting in clinical signs of hypoadrenocorticism. Clinical signs may be seen more often following a stressful event in these patients.

Hypoadrenocorticism in Dogs 5

D. Females appear to be predisposed in some studies, while other studies reveal a more equal distribution between the sexes.E. Dogs diagnosed with isolated glucocorticoid deficiency have a similar signalment to those with com-bined mineralocorticoid/glucocorticoid deficiency. As a population, however, dogs with atypical Addison’s tend to be 2–3 years older at diagnosis compared to those with typical Addison’s.

III. Clinical SignsA. The clinical manifestation of hypoadrenocorticism is highly variable in presenting complaint, chronic-ity, and severity. Some dogs present for chronic clinical signs, whereas others present more acutely in “Addisonian crisis.” Rigid rules differentiating acute from chronic hypoadrenocorticism do not exist; the pathophysiology is the same, and these presentations represent a continuum of disease progression. If not diagnosed and treated early in the course of the disease, many dogs with chronic signs will decompensate and present in crisis. However, they will be discussed separately, since initial treatment differs. Likewise, dogs with isolated cortisol deficiency (atypical hypoadrenocorticism) will also be discussed separately in order to highlight the contrasting features.

1. Chronic hypoadrenocorticism:a. Addison’s disease often causes vague, nonspecific clinical signs that can be confused with other diseases, thus earning it the moniker “The Great Pretender” (Table 1.1). Most patients experience lethargy, decreased appetite, and weight loss with varying severity. The owner may report that the patient just is not acting normally. A waxing and waning pattern, with improvement of clinical signs specifically noted following fluid or steroid administration, is common (Schaer and Chen 1983; Herrtage 2000).b. Vomiting and diarrhea are frequently reported, with or without concurrent melena. Rectal exam-ination may also reveal melena previously unnoticed by owners. Dogs occasionally present with abdominal pain. These gastrointestinal signs are thought to occur due to loss of the “trophic” effects of cortisol on the gastrointestinal mucosa. Exacerbation of or onset of gastrointestinal signs follow-ing a stressful event is often noted in dogs later diagnosed with hypoadrenocorticism. Thus, it is critical that hypoadrenocorticism is considered in patients diagnosed with “stress colitis,” particu-larly if the diarrhea is accompanied by melena, vomiting, and/or generalized lethargy and weakness.c. Patients may also exhibit polyuria and polydipsia. This is likely due to a combination of the decreased renal medullary concentration gradient resulting from hyponatremia, and decreased sodium (and, consequently, water) resorption in the collecting ducts of the kidney.d. Some dogs with hypoadrenocorticism present with generalized or hindlimb weakness, which may be the primary presenting complaint (Figure 1.4). Reflexes are generally normal in these dogs. The reason for this weakness is unclear. Generalized debility is a plausible explanation, but some of these dogs have hindlimb weakness only. Another hypothesis is that electrolyte abnormalities lead to aber-rant neuromuscular function. Whatever the cause, hypoadrenocorticism should be considered in patients that are “down in the hindlimbs.”e. Some dogs with hypoadrenocorticism have concurrent megaesophagus. Rarely, regurgitation is the major presenting complaint in dogs with hypoadrenocorticism. The severity of the megaesopha-gus is variable; regurgitation may be noted, but radiographic evidence without clinical signs is also possible. The esophageal dilation seems to be less severe than that seen in other cases of megae-sophagus. Proposed explanations for this megaesophagus include disturbed neuromuscular function caused by electrolyte abnormalities and muscle weakness secondary to cortisol deficiency. Hypoadrenocorticism is one of the few underlying causes of megaesophagus in which appropriate treatment results in the resolution of esophageal abnormalities, so it should be ruled out in all cases of megaesophagus.f. Muscle cramping has been described in two Standard Poodles with hypoadrenocorticism. Again, aber-rant electrolyte concentrations are hypothesized to cause an underlying neuron conduction abnormality.

2. Acute hypoadrenocorticism:a. Approximately 30% of dogs with hypoadrenocorticism present in hypovolemic shock. Any of the clinical signs described for patients with chronic hypoadrenocorticism may be found in dogs with an

6 Clinical Endocrinology of Companion Animals

acute presentation. History may reveal chronic gastrointestinal signs with acute presentation of vomiting and/or diarrhea. Collapse secondary to hypovolemia and/or generalized weakness is not uncommon.b. Classic signs of hypovolemic shock are usually present, including weak pulse, pale mucous membranes, and prolonged capillary refill time; hypothermia occurs occasionally. Heart rate, how-ever, is variable. Whereas most dogs in hypovolemic shock are tachycardic (>160 bpm), patients in hypoadrenocortical crisis often have a normal to decreased heart rate. This is due to the effects of

Figure 1.4 Hypoadrenocorticism is known as “the Great Pretender” because of the variety of presenting complaints and clinical signs seen in patients. this 8-year-old bearded collie presented for hindlimb weakness and collapse. Serum chemistry revealed hyperkalemia and hyponatremia, and aCtH stimulation confirmed hypoadrenocorticism.

Table 1.1 Clinical signs and physical exam findings in dogs with hypoadrenocorticism.

Clinical signs and physical exam findings Incidence (%)

Lethargy/depression 90

Decreased appetite/anorexia 80

Vomiting 80

Weakness 70

Weight loss 45

Diarrhea 40

Waxing/waning illness 40

Dehydration 40

Hypothermia 35

Shaking/shivering 30

Weak pulses 30

Polyuria/polydipsia 25

Melena 15

Painful abdomen 15

Data modified from Willard et al. (1982); Peterson et al. (1996); and Melian and Peterson (1996).

Hypoadrenocorticism in Dogs 7

hyperkalemia in lowering the heart rate. Thus, the presence of a decreased or normal heart rate (“relative bradycardia”) in a patient in hypovolemic shock should raise suspicion of hyperkalemia and hypoadrenocorticism. Rapid treatment and correction of cardiac changes associated with hyper-kalemia is critical for the survival of the patient.c. Melena is frequently present in patients in Addisonian crisis, and may be severe enough to necessitate blood transfusion. Hematochezia is seen less frequently. Melena may be noted on initial exam, or may not be evident until after beginning therapy. Progressively decreasing hematocrit during treatment (more than by hemodilution alone) should increase suspicion of melena, and the possibility of melena should not be excluded due to its initial absence in feces or upon rectal examination. Ileus may decrease gastrointestinal (GI) transit enough to delay its appearance for 1–2 days. It is not uncommon for melena to appear 2–3 days into treatment. For this reason, hospitalization is recommended until the hematocrit stabilizes or increases.d. Generalized muscle weakness results in shaking and/or shivering in some patients.e. Rarely, severe hypoglycemia leads to seizures in dogs with Addison’s disease.

3. Atypical hypoadrenocorticism:a. Dogs with isolated cortisol deficiency generally present with the same nonspecific clinical signs (lethargy, weight loss, and anorexia) as other dogs with hypoadrenocorticism.b. Gastrointestinal signs (vomiting and diarrhea) are also common, and megaesophagus and seizures (secondary to hypoglycemia) have been reported with atypical hypoadrenocorticism as well.c. Atypical Addisonians infrequently present in acute crisis. This is probably because hyperkalemia and hyponatremia do not occur in these dogs. Hypotension is possible, however, as a result of decreased vascular tone in the absence of cortisol. Acute collapse secondary to hypoglycemia and hemorrhagic shock secondary to GI hemorrhage has also been reported in this group of Addisonian patients.d. Patients with atypical Addison’s disease have a slightly longer duration of clinical signs prior to diagnosis. This may be due to the fact that diagnosis is delayed because there are no electrolyte disturbances to stimulate the clinician’s suspicion of hypoadrenocorticism.

IV. DiagnosisA. Chronic hypoadrenocorticism:

1. Most of the diagnostics performed in dogs with hypoadrenocorticism are done early in the workup, often prior to significant suspicion of hypoadrenocorticism. A complete blood count, serum biochemis-try analysis, and urinalysis should be performed in each patient with clinical signs consistent with hypoadrenocorticism (Table 1.2). It is critical that electrolyte analysis is included in the biochemistry panel, as sodium and potassium abnormalities are often the first specific indicators of hypoadrenocorti-cism. Additionally, electrolyte disturbances are common in patients with gastrointestinal signs of any etiology, and need to be addressed during treatment:

a. Serum biochemistry and urinalysis:1) Most dogs with “typical” hypoadrenocorticism are hyperkalemic (90%) and hyponatremic (85%) at diagnosis. Potassium concentration usually remains below 8 mEq/L, but may be as high as 11 mEq/L. Sodium concentrations are usually in the range of 120–140 mEq/L, but may be as low as 100 mEq/L. Some present with one abnormality without the other (e.g., hyperkalemia without hyponatremia). Hypochloremia often parallels hyponatremia and is seen in approxi-mately half of the patients. Electrolyte disturbances are not always present early in the course of disease; they may appear when the patient’s disease progresses, or not at all, as with atypical hypoadrenocorticism.Emphasis is sometimes placed on calculation of the Na+/K+ ratio. The lower the sodium and the higher the potassium concentration, the lower the ratio. The lower the ratio, the higher the likelihood that the patient has Addison’s disease (Adler et al. 2007). However, a high ratio does not rule out hypoadrenocorticism, nor does a low ratio definitively diagnose it; thus, the utility of the ratio is debatable. Any dog with hyponatremia or hyperkalemia should be considered a suspect for hypoadrenocorticism, regardless of the ratio.

8 Clinical Endocrinology of Companion Animals

2) Azotemia is a frequent finding, and is usually prerenal in nature. Both creatinine (increased in 65% of cases) and blood urea nitrogen (BUN) (increased in 90%) concentrations increase as a result of decreased renal perfusion due to hypovolemia; BUN may be further increased by GI blood loss. Phosphorus is also usually increased in azotemic patients (70% of all Addisonians):

a) Despite the prerenal nature of the azotemia, most dogs with hypoadrenocorticism also have a urine-specific gravity

Hypoadrenocorticism in Dogs 9

b. Complete blood count:1) Cortisol released during illness in dogs with normal adrenocortical function often results in the “stress leukogram” of neutrophilia, lymphopenia, monocytosis, and eosinopenia. These changes, particularly lymphopenia, are often absent in dogs with hypoadrenocorticism. Lymphocytosis and eosinophilia, part of the “reverse stress leukogram,” are only present occa-sionally (10% of cases), while the final component, neutropenia, is rarely present. Despite the infrequent occurrence of the reverse stress leukogram, the absence of a stress leukogram in a sick patient should heighten suspicion of hypoadrenocorticism.2) Approximately 30% of dogs are anemic at diagnosis of hypoadrenocorticism, with the proportion increasing to approximately 70% following rehydration. The anemia is typically normochromic, normocytic, nonregenerative, and mild. Dogs with more severe anemia almost always have evidence of gastrointestinal blood loss, even if not evident at presentation.

2. Radiographs and ultrasound are often performed in patients that present for gastrointestinal signs, including most patients with hypoadrenocorticism. Although results are generally nonspecific, there are some findings commonly present in Addisonian dogs:

a. Thoracic radiographs usually reveal nonspecific signs of hypovolemia, including microcardia and decreased size of the caudal vena cava and pulmonary vessels (Figure 1.5). Megaesophagus may also be seen, as discussed above.b. Abdominal radiographs and ultrasound may reveal microhepatica, consistent with hypovolemia. Adrenal gland length and thickness, on average, are lower in Addisonians than in normal dogs (Figure 1.6). However, there is significant overlap between values in normal and Addisonian dogs. One study reported that the length and thickness of the left adrenal in a small group of hypoadreno-cortical dogs was 10.0–19.7 mm (median, 13.1 mm) and 2.2–3.0 mm (median, 2.4 mm), respectively. The same measurements (length, thickness) of the left adrenal in a group of normal dogs were 13.2–26.3 mm (median, 17.4 mm) and 3.0–5.2 mm (median, 4.1 mm). Despite the trend in smaller adrenal gland measurements in hypoadrenocortical patients, the difference in values is not signifi-cant enough to definitively differentiate between normal and Addisonian patients.

Figure 1.5 Microcardia is a nonspecific indicator of hypovolemia, and is frequently seen in dogs with hypoadrenocorticism.

10 Clinical Endocrinology of Companion Animals

3. Specific endocrine tests:a. The ACTH stimulation test is required for definitive diagnosis of hypoadrenocorticism. A supra-physiologic dose of ACTH is given to maximally stimulate the adrenal glands (Figure 1.7). In dogs with normally functioning adrenal glands, ACTH stimulation will result in a significant increase in cortisol concentration. In hypoadrenocortical dogs, minimal to no increase in cortisol concentration will occur:

1) Protocol:a) A baseline blood sample is obtained.b) Synthetic ACTH (cosyntropin or tetracosactrin), 5 µg/kg (0.005 mg/kg) (up to a maximum of 250 µg/dog) is given, intravenously (Lathan et al. 2008).c) A 1 h post-ACTH blood sample is drawn.d) Pre- and post-ACTH samples are submitted for cortisol analysis.e) Due to inconsistent results, compounded ACTH gel is not recommended for the diagnosis of hypoadrenocorticism.f) In canine Addisonian suspects, intravenous administration of cosyntropin is recommended over intramuscular administration due to potentially altered intramuscular absorption in dehydrated and/or hypovolemic patients.

2) Interpretation of the ACTH stimulation test is based on the value of the post-sample:a) A post-sample of < 2.0 µg/dL (55 nmol/L) is consistent with a clinical diagnosis of hypoad-renocorticism. Lack of response to ACTH stimulation demonstrates that the adrenal cortex is incapable of secreting cortisol, even when stimulated with a much higher amount of ACTH than the body produces:

i. The ACTH stimulation test does not differentiate between primary adrenocortical failure and secondary hypoadrenocorticism due to decreased ACTH secretion. Without the trophic effects of ACTH, the adrenal cortex atrophies, disabling a response to exogenous ACTH. Thus, dogs with primary and secondary hypoadrenocorticism both fail the ACTH stimulation test.ii. Patients with iatrogenic hypoadrenocorticism, resulting from acute withdrawal following prolonged administration of exogenous glucocorticoids, will also have a post-stimulation cortisol concentration < 2.0 µg/kg (55 nmol/L). However, these patients should be easy to differentiate based on historical evidence of glucocorticoid administration.

Figure 1.6 (a) abdominal ultrasound often identifies very small adrenal glands in dogs with hypoadrenocorticism. Note how thin this left adrenal gland is (3.3 mm), compared to the one from a normal dog in (b). (b) Note the peanut shape and width (6.7 mm) of this normal left adrenal gland, compared to the gland from an addisonian dog in (a). (Images provided by Drs. erin Brinkman and erica Baravik.)

(a) (b)

Hypoadrenocorticism in Dogs 11

b) A post-sample >2 µg/dL (55 nmol/L) rules out the clinical diagnosis of hypoadrenocorti-cism in most patients.c) Administration of glucocorticoids prior to the ACTH stimulation test can alter the test in two different ways:

i. Several synthetic glucocorticoids, including prednisone and methylprednisolone, cross-react with the cortisol assay. Thus, both the pre- and post-stimulation cortisol concentra-tions will be falsely elevated following administration of other glucocorticoids. To avoid this, the only glucocorticoids that should be given near the time of the test are dexametha-sone and triamcinolone. Short-acting glucocorticoids, such as prednisone or methylpredni-solone succinate, should be withheld for 12–24 h before the test. Longer-acting repositol steroids, such as methylprednisolone acetate, may cross-react with the assay for up to 4 weeks following administration. If glucocorticoid supplementation is necessary prior to completion of the ACTH stimulation test, dexamethasone or triamcinolone should be given.ii. Short-term administration of glucocorticoids within a month of the test may lead to decreased response to ACTH, depending on patient sensitivity, dosage, and duration of treatment. Exogenous glucocorticoid administration (oral or topical) inhibits the release of endogenous ACTH, which causes atrophy of the adrenal cortex. Following removal of the source of exogenous glucocorticoid, the adrenocortical function slowly recovers. However, if an ACTH stimulation test is performed prior to full recovery, the post-stimulation corti-sol may be below normal. A post-ACTH cortisol concentration between 2 µg/dL (55 nmol/L) and 5 µg/dL (138 nmol/L) is often the result of recent steroid administration as compared to spontaneous hypoadrenocorticism:

Figure 1.7 an aCtH stimulation test is required for definitive diagnosis of hypoadrenocorticism. In order to avoid problems with absorption, synthetic aCtH (cosyntropin) is given intravenously in addison’s disease suspects.

12 Clinical Endocrinology of Companion Animals

i) Chronic administration of glucocorticoids may lead to suppression of the hypothalamic pituitary axis (HPA) and subsequent decreased response to ACTH for more than a month following discontinuation of the medication.

3) For the diagnosis of hypoadrenocorticism, the use of synthetic ACTH (cosyntropin or tetra-cosactrin) is recommended. Compounded gel formulations are available, but testing results are not as consistent with the gels as they are with synthetic ACTH:

a) If compounded ACTH gel must be used, it is recommended to obtain two post-stimulation cortisol samples at 1 and 2 h, due to inconsistent results from the use of the gel.

4) After a 250 µg vial of cosyntropin or tetracosactrin is opened, it can be frozen in plastic syringes and stored for up to 6 months. ACTH binds to glass, so glass syringes should not be used. Freezing in 50 µg aliquots allows dosing for 10 kg dogs with each syringe and minimizes waste. Once thawed, cosyntropin should not be refrozen; a frost-free freezer should NOT be used because of the freeze/thaw cycles.

b. A baseline cortisol concentration is a relatively inexpensive way to rule out hypoadrenocorticism. In almost all patients with hypoadrenocorticism, a baseline cortisol sample will be < 2 µg/dL (55 nmol/L) (often 2 µg/dL (55 nmol/L) rules out hypoadrenocorticism in a given patient. However, since normal dogs can have baseline cortisol samples < 2 µg/dL (55 nmol/L), an ACTH stimulation test MUST be performed to confirm hypoad-renocorticism. A baseline cortisol concentration can only be used to rule out hypoadrenocorticism—NOT to confirm it:

1) In rare cases, a patient with clinical hypoadrenocorticism may have pre- and post-stimulation cortisol values between 2 µg/dL (55 nmol/L) and 3 µg/dL (83 nmol/L). Therefore, strong clinical suspicion of hypoadrenocorticism would mandate an ACTH stimulation test in a dog with base-line values between 2 µg/dL (55 nmol/L) and 3 µg/dL (83 nmol/L).

B. Acute hypoadrenocorticism:1. Patients presenting in hypoadrenocortical crisis have similar diagnostic findings as patients with chronic clinical signs (see above). However, abnormalities are often more severe and can be immediately life-threatening (Figure 1.8):

a. Hyperkalemia and hyponatremia are often marked in patients in crisis. Hyponatremia results in weakness, but severe hyperkalemia may be immediately life-threatening. Individual patients vary in susceptibility to the debilitating effects of hyperkalemia, but potassium concentrations less than 7.0 mEq/L generally cause few specific clinical signs. Values between 7.0 and 9 mEq/L result in weak-ness and moderate to severe cardiac dysfunction, and may be fatal. Values >9.0 mEq/L usually lead to severe cardiac dysfunction and are often fatal:

1) Cardiac function in these patients should be monitored by electrocardiogram (ECG). Although ECG changes do not correlate exactly with specific potassium concentrations, they tend to appear in the following order, with increasing severity of hyperkalemia:

a) Increased T-wave amplitude.b) Shortened Q–T interval.c) Decreased P-wave amplitude.d) Prolonged P–R interval.e) Absent P-wave (sinoatrial standstill).f) Severe bradycardia.g) Asystole.h) Bizarre QRS complexes, including paroxysmal ventricular tachycardia and ventricular fibrillation, may also be seen.

b. Most patients in Addisonian crisis will have significant prerenal azotemia on presentation, which resolves upon correction of hypovolemia. Severe or prolonged hypovolemia, however, can result in ischemic renal damage secondary to hypoperfusion. If tubular epithelial damage results from the ischemia, renal azotemia may occur; however, with appropriate supportive care most patients fully recover renal function. Severe gastrointestinal blood loss is more common in patients in crisis, and may also lead to more severe azotemia (increased BUN).